Acute Myeloid Leukemia

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    • Acute Myeloid Leukemia
      • a tumor of hematopoietic progenitors
      • caused by acquired oncogenic mutations that impede differentiation, leading to the accumulation of immature myeloid blasts in the marrow.
      • The arrest in myeloid development leads to marrow failure
      • AML peaks after 60 years of age
      • Classification.
        • AML WITH GENETIC ABERRATIONS
          • AML with t(8;21)(q22;q22); CBFα/ETO fusion gene   (MCQ)
            • Favorable      prognosis
            • FAB –M2 (MCQ)       
            • Full range of myelocytic maturation
            • Auer rods easily found (MCQ)
            • abnormal cytoplasmic granules
          • AML with inv(16)(p13;q22); CBFβ/MYH11 fusion gene (MCQ)
            • Favorable       prognosis
            • M4eo 
            • Myelocytic and monocytic differentiation
            • abnormal eosinophilic precursors with abnormal basophilic granules (MCQ)
          • AML with t(15;17)(q22;11-12); RARα/PML fusion gene(MCQ)
            • Intermediate prognosis       
            • M3, M3v        
            • Numerous Auer rods, often in bundles within individual progranulocytes (MCQ)
            • primary granules usually very prominent in M3 subtype
            • high incidence of DIC (MCQ)
          • AML with t(11q23;v); diverse MLL fusion genes
            • Poor prognosis        
            • M4, M5
          • AML with normal cytogenetics and mutated NPM    
            • Favorable  prognosis
        • AML WITH MDS-LIKE FEATURES
          • With prior MDS
            • Poor prognosis        
          • AML with multilineage dysplasia
            • Poor prognosis                    
          • AML with MDS-like cytogenetic aberrations
            • Poor prognosis                    
            • Associated with 5q-, 7q-, 20q-aberrations (MCQ)
        • AML, THERAPY-RELATED        
          • Very poor prognosis
          • If following alkylator therapy or radiation therapy
            • 2- to 8-year latency period
            • MDS-like cytogenetic aberrations (e.g., 5q-, 7q-) (MCQ)
          • if following topoisomerase II inhibitor (e.g., etoposide) therapy,
            • 1 to 3-year latency
            • translocations involving MLL (11q23)
        • AML, NOT OTHERWISE SPECIFIED
          • AML, minimally differentiated – M0
          • AML without maturation – M1
          • AML with myelocytic maturation- M2
          • AML with myelomonocytic maturation- M4
          • AML with monocytic maturation -M5a, M5b
          • AML with erythroid maturation -M6a, M6b
          • AML with megakaryocytic maturation- M7
            • most common AML in Down syndrome (MCQ)
            • often accompanied by marrow fibrosis(MCQ)
      • Morphology.
        • The diagnosis of AML is based on the presence of at least 20% myeloid blasts in the bone marrow
        • Myeloblasts
          • have delicate nuclear chromatin
          • two to four nucleoli
          • more voluminous cytoplasm than lymphoblasts
          • The cytoplasm often contains fine, peroxidase-positive azurophilic granules. (MCQ)
          • Auer rods, are present in many cases(MCQ)
          • distinctive needle-like azurophilic granules, (MCQ)
          • they are particularly numerous in AML with the t(15;17) (acute promyelocytic leukemia) (MCQ)
        • Monoblasts
          • have folded or lobulated nuclei
          • lack Auer rods
          • are nonspecific esterase-positive(MCQ)
        • Why is a bone marrow examination is essential in pancytopenic patients ? (MCQ)
          • to exclude acute leukemia
          • Occasionally, blasts are entirely absent from the blood (aleukemic leukemia).
      • Cytogenetics.
        • Cytogenetic analysis has a central role in the classification of AML.
        • AMLs arising de novo in younger adults
          • commonly associated with balanced chromosomal translocations, particularly t(8;21), inv(16), and t(15;17) (MCQ)
        • AMLs following MDS or exposure to DNA-damaging agents (such as chemotherapy or radiation therapy)
          • often have deletions or monosomies involving chromosomes 5 and 7 (MCQ)
          • usually lack chromosomal translocations.
          • The exception to this rule is AML occurring after treatment with topoisomerase II inhibitors, which is strongly associated with translocations involving the MLL gene on chromosome 11q23.
        • AML in the elderly
          • more likely to be associated with “bad” aberrations, such as deletions of chromosomes 5q and 7q. (MCQ)
    • Molecular Pathogenesis.
      • Many recurrent genetic aberrations seen in AML disrupt genes encoding transcription factors that are required for normal myeloid differentiation.
        • t(8;21) and inv(16), (MCQ)
          • disrupt the CBF1α and CBF1β genes, respectively.
          • CBF1α and CBF1β genes encode polypeptides that bind one another to form a CBF1α/CBF1β transcription factor that is required for normal hematopoiesis.
        • t(8;21) and the inv(16) (MCQ)
          • create chimeric genes encoding fusion proteins that interfere with the function of CBF1α/CBF1β
          • block the maturation of myeloid cells
          • mutated tyrosine kinases collaborate with transcription factor aberrations to produce AML.
        • AML with the t(15;17), acute promyelocytic leukemia(MCQ)
          • t(15;17) creates yet another fusion gene that encodes a part of the retinoic acid receptor-α (RARα) fused to a portion of a protein called PML (after the tumor). (MCQ)
          • What is normal RARα function ?
            • In the presence of physiologic amounts of retinoic acid, normal RARα interacts with other transcription factors to activate genes that are needed for granulocytic differentiation
          • What happens with PML-RARα fusion protein ? (MCQ)
            • However, the PML-RARα fusion protein interacts instead with transcriptional repressors, which results in an inhibition of granulocytic maturation
          • AMLs with the t(15;17) also have frequent activating mutations in FLT3(MCQ)
            • What is FLT3 ?
              • FLT3 is a receptor tyrosine kinase (MCQ)
              • It transmits signals that increase cellular proliferation and survival.
          • Why is aberrant tyrosine kinase activation is a common and universal feature of AML.
            • FLT3 mutations are found in Acute Promyelocytic (M3) type AML
            • FLT3 mutations are found in of AML associated with NPM (nucleophosmin) mutations
            • activating mutations in tyrosine kinase receptor, c-KIT, are found in about 25% of AMLs associated with the inv(16) or the t(8;21) (MCQ)
      • Tumors with t(15;17) translocation respond to pharmacologic doses of all-trans retinoic acid (ATRA) – Mechanism (MCQ)
        • ATRA binds to the PML-RARα fusion protein
        • antagonizes Inhibitory effect of PML-RARα fusion protein on the transcription of target genes.
        • Remarkably, the resulting activation of transcription overcomes the block in differentiation
        • within 1 to 2 days the neoplastic promyelocytes begin to differentiate into neutrophils, which rapidly die.
    • Clinical Features.
      • Most patients present within weeks or a few months due to pancytopenia
      • Procoagulants and fibrinolytic factors released by AML with the t(15;17), exacerbate the bleeding tendency(MCQ)
      • tumors with monocytic differentiation often infiltrate the skin (leukemia cutis) and the gingiva(MCQ)
      • CNS spread is less common than in ALL.
      • Myeloblastoma, Granulocytic sarcoma, or Chloroma.
        • AML presents as a localized soft-tissue mass
        • They inevitably progress to full-blown AML over time.
    • Prognosis.
      • AML is a difficult disease to treat.
      • AMLs with t(8;21) or inv(16) (MCQ)
        • have a relatively good prognosis with conventional chemotherapy, particularly in the absence of c-KIT mutations
      • prognosis is dismal for AMLs that (MCQ)
        • follow MDS or genotoxic therapy
        • occur in the elderly
      • AML with poor prognosis is treated with bone marrow transplantation when possible.


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